Acyl sulfamides for treatment of obesity, diabetes and lipid disorders

ABSTRACT

A class of acyl sulfamides comprises compounds that are potent ligands for PPAR gamma and generally have antagonist or partial agonist activity. The compounds may be useful in the treatment, control or prevention of obesity, non-insulin dependent diabetes mellitus (NIDDM), hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, inflammation, and other PPAR gamma mediated diseases, disorders and conditions.

FIELD OF THE INVENTION

[0001] The instant invention is concerned with acyl sulfamides andpharmaceutically acceptable salts and prodrugs thereof and their use astherapeutic. compounds, particularly in the treatment of obesity, ofType 2 diabetes mellitus (often referred to as non-insulin dependentdiabetes, NIDDM), of conditions that are often associated with thesediseases, and of lipid disorders.

BACKGROUND OF THE INVENTION

[0002] Excessive weight, and in extreme cases obesity, is a widespreadmedical problem. This may be due in part to sedentary life styles andpoor diet (high in fats and carbohydrates), as well as to a geneticpredisposition in many cases.

[0003] Pharmaceuticals have been marketed in the past to help controlexcessive weight and obesity. These have typically tried to achieveweight loss by reducing appetite. Drugs used to reduce appetite have notbeen universally successful. Many are stimulants and have been abused,and others have had unexpected, and sometimes serious side effects(e.g., fen-phen). An approach that has so far not been exploitedsuccessfully is the development of pharmaceuticals that controlexcessive weight and obesity using a metabolic approach by modulation ofreceptors that can influence weight gain.

[0004] Diabetes refers to a disease process derived from multiplecausative factors and characterized by elevated levels of plasma glucoseor hyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

[0005] There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

[0006] Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

[0007] The available treatments for type 2 diabetes have recognizedlimitations. While physical exercise and reductions in dietary intake ofcalories will dramatically improve the diabetic condition, compliancewith this treatment is very poor because of well-entrenched sedentarylifestyles and excess food consumption, especially of foods containinghigh amounts of saturated fat. Increasing the plasma level of insulin byadministration of sulfonylureas (e.g. tolbutamide and glipizide), whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin after the response to sulfonylureas fails, willresult in high enough insulin concentrations to stimulate the veryinsulin-resistant tissues. However, dangerously low levels of plasmaglucose can result from these last two treatments, and increasinginsulin resistance due to the even higher plasma insulin levels canoccur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea, respectively.

[0008] The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for a novel mode ofaction in ameliorating many symptoms of type 2 diabetes. These agentssubstantially increase insulin sensitivity in muscle, liver and adiposetissue in several animal models of type 2 diabetes resulting in partialor complete correction of the elevated plasma levels of glucose withoutoccurrence of hypoglycemia.

[0009] Disorders of lipid metabolism or dyslipidemias include variousconditions characterized by abnormal concentrations of one or morelipids (i.e. cholesterol and triglycerides), and/or apolipoproteins(i.e., apolipoproteins A, B, C and E), and/or lipoproteins (i.e., themacromolecular complexes formed by the lipid and the apolipoprotein thatallow lipids to circulate in blood, such as LDL, VLDL and IDL).Cholesterol is mostly carried in Low Density Lipoproteins (LDL), andthis component is commonly known as the “bad” cholesterol because it hasbeen shown that elevations in LDL-cholesterol correlate closely to therisk of coronary heart disease. A smaller component of cholesterol iscarried in the High Density Lipoproteins and is commonly known as the“good” cholesterol. In fact, it is known that the primary function ofHDL is to accept cholesterol deposited in the arterial wall and totransport it back to the liver for disposal through the intestine.Although it is desirable to lower elevated levels of LDL cholesterol, itis also desirable to increase levels of HDL cholesterol. Generally, ithas been found that increased levels of HDL are associated with lowerrisk for coronary heart disease (CHD). See, for example, Gordon, et al.,Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. England J. Med.,325, 373-381 (1991); and Kannel, et al., Ann. Internal Med., 90, 85-91(1979). An example of an HDL raising agent is nicotinic acid, a drugwith limited utility because doses that achieve HDL raising areassociated with undesirable effects, such as flushing.

[0010] Dyslipidemias were originally classified by Fredrickson accordingto the combination of alterations mentioned above. The Fredricksonclassification includes 6 phenotypes (i.e., I, IIa, IIb, HI, IV and V)with the most common being the isolated hypercholesterolemia (or typeIIa) which is usually accompanied by elevated concentrations of totaland LDL cholesterol. The initial treatment for hypercholesterolemia isoften to modify the diet to one low in fat and cholesterol, coupled withappropriate physical exercise, followed by drug therapy whenLDL-lowering goals are not met by diet and exercise alone

[0011] A second common form of dyslipidemia is the mixed or combinedhyperlipidemia or type IIb and III of the Fredrickson classification.This dyslipidemia is often prevalent in patients with type 2 diabetes,obesity and the metabolic syndrome. In this dyslipidemia there aremodest elevations of LDL-cholesterol, accompanied by more pronouncedelevations of small dense LDL-cholesterol particles, VLDL and/or IDL(i.e., triglyceride rich lipoproteins), and total triglycerides. Inaddition, concentrations of HDL are often low.

[0012] Peroxisome proliferator activated receptors (PPARs) haveattracted considerable scientific attention in the last few years inpart because of their emergence as the molecular target of a new groupof Type II (non-insulin dependent) diabetes (NIDDM) medicines, theglitazones. Three sub-types of peroxisome proliferator activatedreceptor (PPAR) have been discovered and described; they are peroxisomeproliferator activated receptor gamma (PPARγ), peroxisome proliferatoractivated receptor alpha (PPARα) and peroxisome proliferator activatedreceptor delta (PPARδ).

[0013] The PPARγ receptor subtypes are involved in activating theprogram of adipocyte differentiation and are not involved in stimulatingperoxisome proliferation in the liver. There are two known proteinisoforms of PPARγ: PPARγ1 and PPARγ2 which differ only in that PPARγ2contains an additional 28 amino acids present at the amino terminus. TheDNA sequences for the human isotypes are described in Elbrecht, et al.,BBRC 224;431-437 (1996). In mice, PPARγ2 is expressed specifically infat cells. Tontonoz et al., Cell 79: 1147-1156 (1994) provide evidenceto show that one physiological role of PPARγ2 is to induce adipocytedifferentiation. As with other members of the nuclear hormone receptorsuperfamily, PPARγ2 regulates the expression of genes throughinteraction with other proteins and binding to hormone responseelements, for example in the 5′ flanking regions of responsive genes. Anexample of a PPARγ2 responsive gene is the tissue-specific adipocyte P2gene. Although peroxisome proliferators, including the fibrates andfatty acids, activate the transcriptional activity of PPAR's, onlyprostaglandin J₂ derivatives have been identified as potential naturalligands of the PPARγ subtype, which also binds thiazolidinedioneantidiabetic agents with high affinity.

[0014] It is generally believed that glitazones exert their effects bybinding to the peroxisome proliferator activated receptor (PPAR) familyof receptors, controlling certain transcription elements having to dowith the biological entities listed above. See Hulin et al., CurrentPharm. Design (1996) 2, 85-102. A number of glitazones that are PPARagonists have been approved for use in the treatment of diabetes. Theseinclude troglitazone, rosiglitazone and pioglitazone, all of which areprimarily or exclusively PPARγ agonists. Many of the newer PPAR agoniststhat are currently under development or are in clinical trials have dualPPARα and γ activity. These are expected to improve both insulinsensitivity and the lipid profile in patients having NIDDM. Althoughglitazones are beneficial in the treatment of NIDDM, there have beensome serious adverse events associated with the use of the compounds.The most serious of these has been liver toxicity, which has resulted ina number of deaths. The most serious problems have occurred usingtroglitazone. Because of the problems that have occurred with theglitazones, researchers in a number of laboratories have beeninvestigating classes of PPAR agonists that are not glitazones and donot contain 1,3-thiazolidinedione moieties. In addition some ligandsbehave as partial agonists of PPARγ. There are some reasons to believethat such compounds might exhibit modulated pharmacology. As such therehas been growing interest in such compounds.

[0015] Several patent applications and publications have suggested thatPPAR-gamma antagonists or partial agonists may be effective in thetreatment of obesity. See WO 96/40128, WO 97/10813, and J. Oberfield, etal., Proc. Nat. Acad. Sci. USA, Vol. 96, pp 6102-6106 (1999). Also,since PPAR-gamma agonists are used in the treatment of NIDDM, andobesity generally accompanies NIDDM, these compounds are generally alsoclaimed as useful in the treatment of obesity.

[0016] PPARα is activated by a number of medium and long-chain fattyacids, and it is involved in stimulating β-oxidation of fatty acids.PPARα is also associated with the activity of fibrates and fatty acidsin rodents and humans. Fibric acid derivatives such as clofibrate,fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, aswell as gemfibrozil, each of which are PPARα ligands and/or activators,produce a substantial reduction in plasma triglycerides as well as someincrease in HDL. The effects on LDL cholesterol are inconsistent andmight depend upon the compound and/or the dyslipidemic phenotype. Forthese reasons, this class of compounds has been primarily used to treathypertriglyceridemia (i.e, Fredrickson Type IV and V) and/or mixedhyperlipidemia. It is important to note that there may exist a degree ofoverlap between the functions of PPARγ and PPARα.

[0017] The human nuclear receptor gene PPARδ (hPPARδ) has been clonedfrom a human osteosarcoma cell cDNA library and is fully described in A.Schmidt et al., Molecular Endocrinology, 6 :1634-1641 (1992). It shouldbe noted that PPARδ is also referred to in the literature as PPARβ andas NUC1, and each of these names refers to the same receptor; in Schmidtet al. the receptor is referred to as NUC 1. In W096/01430, a human PPARsubtype, hNUC1B, is disclosed. The amino acid sequence of hNUC1B differsfrom human PPARδ (referred to therein as hNUC1) by one amino acid, i.e.,alanine at position 292. Based on in vivo experiments described therein,the authors suggest that hNUC1B protein represses hPPARα and thyroidhormone receptor protein activity. It has been disclosed in W097/28149that agonists of PPARδ are useful in raising HDL plasma levels.W097/27857, 97/28115,97/28137 and 97/27847 disclose compounds that areuseful as antidiabetic, antiobesity, anti-atherosclerosis andantihyperlipidemic agents, and which may exert their effect throughactivation of PPARs.

SUMMARY OF THE INVENTION

[0018] The class of compounds described herein is a new class of PPARligands that do not contain a 1,3-thiazolidinedione moiety and thereforeare not glitazones. The compounds in this class are primarily PPARγantagonists or partial agonists. Some of the compounds may also exhibitsome level of PPARα agonism. These compounds are useful in thetreatment, control and/or prevention of obesity, diabetes,hyperglycemia, insulin resistance, mixed or diabetic dyslipidemia, otherlipid disorders, atherosclerosis, vascular restenosis, inflammatoryconditions, neoplastic conditions, and other PPARγ mediated diseases,disorders and conditions.

[0019] The present invention provides compounds having the structure ofFormula I:

[0020] including pharmaceutically acceptable salts and prodrugs thereof,wherein

[0021] X is selected from CH and N;

[0022] R₁ is —(CH₂)_(a)(Y₁)_(b)(Z)_(c)(Y₂)_(d)R₄;

[0023] a, b, c, and d are each independently 0 or 1, with the provisothat if c is 0, then b and d are not both 1;

[0024] Y₁ and Y₂ are each independently O or NH;

[0025] Z is selected from C(O) and S(O)₂;

[0026] R₂ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ Cycloalkyl, C₆₋₁₀ Aryl, Heteroaryl, and Heterocycle, and R₂ isoptionally substituted with 1-5 groups R₃;

[0027] Each R₃ is independently selected from H, halogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ Aryl, —OC₁₋₆ alkyl, —OC₂₋₆ alkenyl,—OC₂₋₆ alkynyl, —OC₆₋₁₀ Aryl, C₃₋₆ Cycloalkyl, Heteroaryl, Heterocycle,CN, NO₂, S(O)_(m)R₄, SO₂NHR₄, SO₂N RR, CO₂H, and CONFR₄, wherein eachalkyl, alkenyl, alkynyl, Aryl, -Oalkyl, -Oalkenyl, -Oalkynyl, -Oaryl,Cycloalkyl, Heteroaryl, and Heterocycle is optionally substituted with1-5 substituents independently selected from halogen, —OCF₃, —OCH₃, CF₃and CH₃;

[0028] Each R₄ is independently selected from the group consisting of H,C₁₋₁₀ alkyl, C₃₋₁₀ Cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₆₋₁₀ Aryl,Heterocycle, and Heteroaryl, wherein R₄ is optionally substituted with1-3 groups R₅;

[0029] Each R₅ is independently selected from halogen, C₁₋₆ alkyl, C₆₋₁₀Aryl, —OC₁₋₆ alkyl, —OC₂₋₆ alkenyl, —OC₂₋₆ alkynyl, —OC₆₋₁₀ Aryl, C₃₋₆Cycloalkyl, CN, NO₂, CO₂H, CO₂C₁-C₆alkyl and CONH₂, wherein each alkyl,Aryl, -Oalkyl, -Oalkenyl, -Oalkynyl, -Oaryl, Cycloalkyl and CO₂alkyl isoptionally substituted with 1-5 substituents independently selected fromhalogen, —OCF₃, —OCH₃, CF₃ and CH₃;

[0030] m is 0, 1 or 2;

[0031] Each alkyl, alkenyl and alkynyl group may be linear or branched;

[0032] Cycloalkyl is a saturated or partly saturated monocyclic orbicyclic carbocyclic ring system;

[0033] Aryl is a monocyclic or bicyclic carbocyclic aromatic ringsystem;

[0034] Heterocycle is a fully saturated or partially saturatedmonocyclic or bicyclic ring system comprising at least one heteroatomselected from N, S and O in the ring and comprising 4 to 11 atoms in thering; and

[0035] Heteroaryl is a monocyclic or bicyclic aromatic ring systemcomprising at least one ring heteroatom selected from N, O and S andcomprising 4-11 atoms in the ring or rings.

[0036] The compounds are expected to be efficacious in the treatment,control and/or prevention of obesity and non-insulin dependent diabetesmellitus (NIDDM) in humans and in the treatment, control, and/orprevention of hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertrigyceridemia, atherosclerosis, vascular restenosis, inflammatoryconditions, neoplastic conditions, and other PPARγ mediated diseases,disorders and conditions. Many of these latter conditions listed above(hyperlipidemia, dyslipidemia, etc.) are often associated with NIDDM,but may also occur independently of NIDDM.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The invention has numerous embodiments. Several subsets ofcompounds are described below.

[0038] One group of compounds comprises compounds having formula I inwhich X is CH.

[0039] A preferred subset of the above group of compounds in which X isCH comprises compounds in which R₁ is selected from CH₂OCONHR₄,CH₂OCOOR₄, CH₂OCOR₄, CH₂OR₄, CH₂NHCOOR₄, CH₂NHCONHR₄, CH₂NHCOR₄,CH₂NHS(O)₂NHR₄, CH₂NHS(O)₂R₄, CONHR₄, S(O)₂NHR₄, OCONHR₄, NHCOOR₄,NHCONHR₄, NHS(O)₂NHR₄, NHCOR₄, and NHS(O)₂R₄.

[0040] A preferred subgroup of the above subset of compounds includescompounds in which R₁ is CH₂OCONHR₄, CH₂OCOOR₄, CH₂OCOR₄, CH₂OR₄,CH₂NHCOOR₄, CH₂NHCONHR₄, CH₂NHCOR₄, CH₂NHS(O)₂NHR₄, or CH₂NHS(O)₂R₄.

[0041] Another group of compounds comprises those compounds havingFormula I in which X is N. A preferred subgroup comprises compounds inwhich R₁ is selected from CONHR₄, COOR₄, COR₄, S(O)₂R₄, and S(O)₂NHR₄.

[0042] Preferred embodiments also include compounds in which R₂ isselected from C₁₋₆ alkyl, CH₂C₃₋₁₀ Cycloalkyl and CH₂C₆₋₁₀ Aryl, whereinR₂ is optionally substituted with 1-3 halogens, and Cycloalkyl and Arylare optionally substituted with 1-3 groups R₃. Preferred compounds fromthese embodiments include compounds in which R₂ is CH₂phenyl, wherephenyl is optionally substituted with 1-3 groups R₃.

[0043] Another preferred embodiment includes compounds in which each R₃is independently selected from the group consisting of H, halogen, C₁₋₆alkyl, and —OC₁₋₆ alkyl, wherein alkyl and -Oalkyl are optionallysubstituted with 1-5 fluorine atoms.

[0044] Another preferred embodiment includes compounds having Formula Iin which each R₄ is independently selected from the group consisting ofH, C₁₋₆ alkyl, C₃₋₆ Cycloalkyl, phenyl, and Heteroaryl, whereinCycloalkyl is a monocyclic carbocyclic ring and Heteroaryl is amonocyclic 5 or 6-membered aromatic ring having at least one heteroatomselected from O, S and N in the ring, and R₄ is optionally substitutedwith 1-3 R₅. In highly preferred compounds having Formula I, R₄ isselected from the group consisting of H, phenyl and C₁₋₆alkyl, wherephenyl is optionally substituted with 1-3 groups independently selectedfrom halogen, CH₃, CF₃, —OCH₃ and —OCF₃, and alkyl is optionallysubstituted with 1-3 halogens and/or one phenyl, which is optionallysubstituted with 1-3 groups independently selected from halogen, CH₃,CF₃, —OCH₃ and —OCF₃.

[0045] A preferred group comprises compounds in which:

[0046] when X is CH, R₁ is selected from CH₂OCONHR₄, CH₂OCOOR₄,CH₂OCOR₄, CH₂OR₄, CH₂NHCOOR₄, CH₂NHCONHR₄, CH₂NHCOR₄, CH₂NHS(O)₂NHR₄,and CH₂NHS(O)₂R₄, and

[0047] when X is N, R₁ is selected from CONHR₄, COOR₄, COR₄, S(O)₂R₄,and S(O)₂NHR₄. In these groups, regardless of whether X is CH or N:

[0048] R₂ is benzyl or C₁₋₆ alkyl, and R₂ is optionally substituted with1-3 R₃;

[0049] R₃ is selected from H, halogen, C₁₋₆alkyl, —OCH₃ and —OCF₃,wherein alkyl is optionally substituted with 1-3 halogens; and

[0050] Each R₄ is independently selected from H, phenyl and C₁₋₆alkyl,wherein phenyl is optionally substituted with 1-3 groups independentlyselected from halogen, CH₃, CF₃, —OCH₃ and —OCF₃ , and alkyl isoptionally substituted with 1-3 halogens and/or 1 phenyl, which isoptionally substituted with 1-3 groups independently selected fromhalogen, CH₃, CF₃, —OCH₃ and —OCF₃.

[0051] Particularly preferred groups of compounds include thosecompounds having Formula I in which R₂ is benzyl.

[0052] The compounds of Formula I can have up to 3 substituents R₃ onthe benzamide ring. More typically, there are 1-2 groups R3 on thebenzamide ring.

[0053] Specific examples of compounds of this invention, which alsoinclude pharmaceutically acceptable salts and prodrugs, are provided asExamples 1-20, named below:

[0054] 1.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylbenzoate;

[0055] 2.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylpentanoate;

[0056] 3.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylphenylcarbamate;

[0057] 4.(4-{[({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylphenylcarbamate;

[0058] 5.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylbenzylcarbamate;

[0059] 6.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl2-phenylethycarbamate

[0060] 7.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexy)methyl3-methoxyphenylcarbamate;

[0061] 8.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylbutylcarbamate;

[0062] 9.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl1-methylbutylcarbamate;

[0063] 10.N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]-N-({4-[(pentyloxy)methyl]cyclohexyl}methyl)sulfamide;

[0064] 11.N-benzyl-4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}-sulfonyl)amino]methyl}cyclohexanecarboxamide;

[0065] 12.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]-N′-phenylurea;

[0066] 13.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]pentanamide;

[0067] 14.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]benzamide;

[0068] 15.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]-N′-butylurea;

[0069] 16. Butyl(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylcarbamate;

[0070] 17.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]benzenesulfonamide;

[0071] 18.(4-{[({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)(ethyl)amino]methyl}cyclohexyl)methylphenylcarbamate;

[0072] 19.{4-[(benzyl{[(3,5-dimethylbenzoyl)amino]sulfonyl}amino)methyl]cyclohexyl}methylphenylcarbamate; and

[0073] 20.4-(benzyl-{[(4-t-butylbenzoyl)amino]sulfonyl}aminomethyl)-1-piperidinecarboxylicacid phenylmethyl ester.

[0074] The structures of specific compounds are shown in the followingTable of Examples. Pharmaceutically acceptable salts and prodrugs arealso included: EXAMPLE No. STRUCTURE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

[0075] The invention further includes pharmaceutical compositionscomprising any of the compounds of formula I as described above, and anyof the specific compounds exemplified herein, and a pharmaceuticallyacceptable carrier.

[0076] The compounds as defined above are useful in the followingmethods of treating, controlling, and preventing diseases, and may alsohave utility in treating certain other diseases and conditions that arenot listed below.

[0077] (1) a method for treating, controlling, or preventing obesity ina mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I;

[0078] (2) a method for treating, controlling or preventing diabetesmellitus, and particularly non-insulin dependent diabetes mellitus, in amammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I;

[0079] (3) a method for treating, controlling, or preventinghyperglycemia in a mammalian patient in need of such treatment whichcomprises administering to the patient a therapeutically effectiveamount of a compound of Formula I;

[0080] (4) a method for treating, controlling, or preventing lipiddisorders, hyperlipidemia, or low HDL in a mammalian patient in need ofsuch treatment which comprises administering to the patient atherapeutically effective amount of a compound of Formula I;

[0081] (5) a method for treating, controlling, or preventinghypercholesterolemia in a mammalian patient in need of such treatmentwhich comprises administering to the patient a therapeutically effectiveamount of a compound of Formula I;

[0082] (6) a method for treating, controlling, or preventinghypertriglyceridemia in a mammalian patient in need of such treatmentwhich comprises administering to the patient a therapeutically effectiveamount of a compound of Formula I;

[0083] (7) a method for treating, controlling, or preventingdyslipidemia, including low HDL cholesterol, in a mammalian patient inneed of such treatment which comprises administering to the patient atherapeutically effective amount of a compound of Formula I;

[0084] (8) a method for treating, controlling, or preventingatherosclerosis in a mammalian patient in need of such treatment whichcomprises administering to the patient a therapeutically effectiveamount of a compound of Formula I. It is understood that the sequellaeof atherosclerosis (angina, claudication, heart attack, stroke, etc.)are thereby treated.

[0085] Definitions

[0086] “Ac” is acetyl, which is CH₃C(O)—.

[0087] “Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy or alkanoyl, means carbon chains which may be linear or branchedor combinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike.

[0088] “Alkenyl” means carbon chains which contain at least onecarbon-carbon double bond, and which may be linear or branched orcombinations thereof. Examples of alkenyl include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

[0089] “Alkynyl” means carbon chains which contain at least onecarbon-carbon triple bond, and which may be linear or branched orcombinations thereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

[0090] “Cycloalkyl” means a saturated or partly saturated monocyclic orbicyclic carbocyclic ring system having from 3 to 12 carbon atoms,unless otherwise defined. The term also can include a monocyclic ringfused to an aryl group or other ring system. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, and the like.

[0091] “Aryl” (and “arylene”) means mono-or bicyclic aromatic ringscontaining only carbon ring atoms. Aryl groups that are described hereinare 6-10-membered monocyclic or bicyclic ring systems, unless otherwisedefined, and are preferably phenyl or naphthyl. Phenyl is mostpreferred. The term “aryl” also may describe a phenyl group that isfused to a monocyclic cycloalkyl or monocyclic heterocyclic group.“Heterocycle” and “heterocyclic” means a fully or partially saturatedmonocyclic or bicyclic ring system containing at least one heteroatomselected from N, S and O in the ring, where the ring system has 4 to 11atoms, except where defined otherwise. S may also have 1-2 O atoms boundto it that are not in the ring itself. Examples of aryl substituentsinclude phenyl and naphthyl. Fused aryls include the phenyl ring ofindanyl, indenyl, and tetrahydronaphthyl. Examples of aryl fused toheterocyclic groups include 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, and the like. Examples of heterocycles includetetrahydrofuran, piperazine, tetrahydropyran, and morpholine.

[0092] “Heteroaryl” (and heteroarylene) means a mono-or bicyclicaromatic ring system containing 4-11 atoms in the ring or rings,including at least one ring heteroatom selected from N, O and S in thering or rings (including SO and SO₂, where the O atoms are not in thering. Heteroaryl as a substituent also includes bicyclic aromatic ringshaving a heteroaromatic ring fused to a carbocyclic aromatic ring, suchas benzene. Examples of heteroaryl include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl,quinolyl, indolyl, isoquinolyl, dibenzofuran and the like.

[0093] “Halogen” includes fluorine, chlorine, bromine and iodine.

[0094] The term “composition,” as in pharmaceutical composition, isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

[0095] In the description above and elsewhere, including the claims,when something is described as being “optional,” such as one or moresubstituents or compounds from one or more lists of optionalsubstituents or compounds, one of the options is that the substituent orcompound may be absent.

[0096] Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

[0097] Compounds of Formula I may contain one or more asymmetric centersand can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

[0098] In compounds of Formula I in which X is CH, the groups that arein the 1,4-positions of the cyclohexyl ring can be cis or trans relativeto each other. Both cis and trans isomers are included in the compoundsdefined by Formula I. The trans compounds are believed to be more activeand are preferred.

[0099] Some of the compounds described herein may contain olefinicdouble bonds, and unless specified otherwise, are meant to include bothE and Z geometric isomers.

[0100] Some of the compounds described herein may exist with differentpoints of attachment of hydrogen accompanied by one or more double bondshifts, referred to as tautomers. For example, a ketone and its enolform are keto-enol tautomers. The individual tautomers as well asmixtures thereof are encompassed with compounds of Formula I.

[0101] If desired, racemic mixtures of compounds of Formula I may beseparated by the coupling of a racemic mixture of the compounds ofFormula I to an enantiomerically pure compound to form a diastereomericmixture, followed by separation of the individual diastereomers bystandard methods, such as fractional crystallization or chromatography.The coupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds of Formula I canalso be separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

[0102] Alternatively, any enantiomer of a compound of the generalFormula I may be obtained by stereoselective synthesis using opticallypure starting materials or reagents of known configuration. Such methodsare well known in the art.

[0103] Compounds of Formula I that have more than one asymmetric centerand that occur as mixtures of diasteromers can similarly be separatedinto single diasteromers by standard methods, and these can be furtherseparated to individual enantiomers as described above.

[0104] Salts

[0105] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases and inorganic or organic acids.Salts derived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

[0106] When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

[0107] It will be understood that, as used herein, references to thecompounds of Formula I are meant to also include the pharmaceuticallyacceptable salts.

[0108] Metabolites—Prodrugs

[0109] Metabolites of the compounds of this invention that aretherapeutically active and that have the structure shown in formula Ialso are within the scope of the claimed parent compounds. Prodrugs,which are compounds that are converted to the claimed compounds as theyare being administered to a patient or after they have been administeredto a patient, are also within the scope of the claimed active compounds.

[0110] Utilities

[0111] Compounds of the present invention are antagonists or partialagonists of PPARγ. Compounds of the present invention are useful intreating, controlling or preventing diseases, disorders or conditions,wherein the treatment is mediated by the modulation of PPAR γ. Oneaspect of the present invention provides a method for the treatment,control or prevention of such diseases, disorders, or conditions in amammal which comprises administering to such mammal a therapeuticallyeffective amount of a compound of Formula I. The compounds areparticularly useful for the treatment of obesity and/or non-insulindependent diabetes mellitus. This is discussed in detail in WO01/30343,which is incorporated by reference into this patent application in itsentirety. The diseases, disorders or conditions for which compounds ofthe present invention are generally useful in treating, controlling orpreventing include, but are not limited to, (1) obesity, (2) diabetesmellitus, and especially non-insulin dependent diabetes mellitus(NIDDM), (3) hyperglycemia, (4) low glucose tolerance, (5) insulinresistance, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia,(9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDLlevels, (12) high LDL levels, (13) atherosclerosis and its sequelae,(14) vascular restenosis, (15) irritable bowel syndrome, (16)inflamatory bowel disease, including Crohn's disease and ulcerativecolitis, (17) other inflammatory conditions, (18) pancreatitis, (19)abdominal obesity, (20) neurodegenerative disease, (21) retinopathy,(22) neoplastic conditions, (23) adipose cell tumors, (24) adipose cellcarcinomas, such as liposarcoma, (25) prostate cancer and other cancers,including gastric, breast, bladder and colon cancers, (26) angiogenesis,(27) Alzheimer's disease, (28) psoriasis, (29) acne vulgaris, (30) otherskin diseases and dermatological conditions modulated by PPAR, (31) highblood pressure, (32) Syndrome X, (33) ovarian hyperandrogenism(polycystic ovarian syndrome), and other disorders where insulinresistance is a component.

[0112] Another aspect of the invention provides a method of treatingcachexia. PPARα is known to be necessary for an appropriate energysparing response to starvation, and inappropriate metabolism and energyutilization is clearly responsible for the wasting of cachexia.

[0113] Another aspect of the invention provides a method of treating avariety of skin diseases and dermatological conditions that aremodulated by PPARα and/or γ0 agonists. These diseases and conditionsinclude psoriasis and acne vulgaris. Examples of other skin diseases anddermatological disorders that may be treated include eczema; lupusassociated skin lesions; dermatitides such as seborrheic dermatitis andsolar dermatitis; keratoses such as seborrheic keratosis, senilekeratosis, actinic keratosis, photo-induced keratosis, and keratosisfollicularis; keloids and prophylaxis against keloid formation, wartsinluding verruca, condyloma, or condyloma accuminatum, and humanpapilloma viral (HPV) infections such as venereal warts, viral warts,molluscum contagiosum, leukoplakia, lichen planus; keratitis, skincancer such as basal cell carcinoma and cutaneous T cell lymphoma, andlocalized benign epidermal tumors (keratoderma, epidermal naevi).

[0114] Another aspect of the invention provides a method of treatinginflammatory conditions, including inflammatory bowel disease, Crohn'sdisease, and ulcerative colitis by administering an effective amount ofa PPAR agonist. Additional inflammatory diseases that may be treatedwith the instant invention include gout, rheumatoid arthritis,osteoarthritis, multiple sclerosis, asthma, ARDS, psoriasis, vasculitis,ischemia/reperfusion injury, frostbite, and related diseases.

[0115] Administration and Dose Ranges

[0116] Any suitable route of administration may be employed forproviding a mammal, especially a human, with an effective dose of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably compounds of Formula I are administered orally.

[0117] The effective dosage of active ingredient employed may varydepending on the particular compound employed, the mode ofadministration, the condition being treated and the severity of thecondition being treated. Such dosage may be ascertained readily by aperson skilled in the art.

[0118] When treating or preventing obesity, diabetes mellitus and/orhyperglycemia or hypertriglyceridemia or other diseases for whichcompounds of Formula I are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 milligram to about 100 milligram perkilogram of animal body weight, preferably given as a single daily doseor in divided doses two to six times a day, or in sustained releaseform. For most large mammals, the total daily dosage is from about 1.0milligrams to about 1000 milligrams, preferably from about 1 milligramsto about 50 milligrams. In the case of a 70 kg adult human, the totaldaily dose will generally be from about 7 milligrams to about 350milligrams. This dosage regimen may be adjusted to provide the optimaltherapeutic response.

[0119] Pharmaceutical Compositions

[0120] Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof as an activeingredient, as well as a pharmaceutically acceptable carrier andoptionally other therapeutic ingredients. The term “pharmaceuticallyacceptable salts” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic bases or acidsand organic bases or acids.

[0121] The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

[0122] In practical use, the compounds of Formula I can be combined asthe active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

[0123] Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit form in which casesolid pharmaceutical carriers are obviously employed. If desired,tablets may be coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

[0124] The tablets, pills, capsules, and the like may also contain abinder such as gum tragacanth, acacia, corn starch or gelatin;excipients such as dicalcium phosphate; a disintegrating agent such ascorn starch, potato starch, alginic acid; a lubricant such as magnesiumstearate; and a sweetening agent such as sucrose, lactose or saccharin.When a dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as a fatty oil.

[0125] Various other materials may be present as coatings or to modifythe physical form of the dosage unit. For instance, tablets may becoated with shellac, sugar or both. A syrup or elixir may contain, inaddition to the active ingredient, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and a flavoring such ascherry or orange flavor.

[0126] Compounds of formula I may also be administered parenterally.Solutions or suspensions of these active compounds can be prepared inwater suitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0127] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0128] Combination Therapy

[0129] Compounds of Formula I may be used in combination with otherdrugs that may also be useful in the treatment, prevention, suppressionor amelioration of the diseases or conditions for which compounds ofFormula I are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapyalso includes therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compound of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

[0130] Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

[0131] (a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like), and compounds disclosed in WO97/27857,97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin andphenformin; (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,and (iv) dipeptidyl peptidase IV (DP-IV) inhibitors;

[0132] (b) insulin or insulin mimetics;

[0133] (c) sulfonylureas such as tolbutamide and glipizide, or relatedmaterials;

[0134] (d) α-glucosidase inhibitors (such as acarbose);

[0135] (e) cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as KRP-297, (vi) inhibitors ofcholesterol absorption, such as for example beta-sitosterol, (vii) acylCoA:cholesterol acyltransferase inhibitors, such as for exampleavasimibe, and (viii) anti-oxidants, such as probucol;

[0136] (f) PPARδ agonists such as those disclosed in WO97/28149;

[0137] (g) antiobesity compounds such as fenfluramine, dexfenfluramine,phentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors, and β₃adrenergic receptor agonists;

[0138] (h) an ileal bile acid transporter inhibitor; and

[0139] (i) agents intended for use in inflammatory conditions such asaspirin, non-steroidal anti-inflammatory drugs, glucocorticoids,azulfidine, and cyclo-oxygenase 2 selective inhibitors.

[0140] The above combinations include combinations of a compound of thepresent invention not only with one other active compound, but also withtwo or more other active compounds. Non-limiting examples includecombinations of compounds having Formula I with two or more activecompounds selected from biguanides, sulfonylureas, HMG-CoA reductaseinhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors,and anti-obesity compounds.

[0141] Biological Assays

[0142] A) PPAR Binding Assays

[0143] For preparation of recombinant human PPARγ, PPARδ, and PPARα:Human PPARγ₂, human PPARδ and human PPARα were expressed as gst-fusionproteins in E. coli. The full length human cDNA for PPARγ₂ was subclonedinto the pGEX-2T expression vector (Pharmacia). The full length humancDNAs for PPARδ and PPARα were subcloned into the pGEX-KT expressionvector (Pharmacia). E. coli containing the respective plasmids werepropagated, induced, and harvested by centrifugation. The resuspendedpellet was broken in a French press and debris was removed bycentrifugation at 12,000×g. Recombinant human PPAR receptors werepurified by affinity chromatography on glutathione sepharose. Afterapplication to the column, and one wash, receptor was eluted withglutathione. Glycerol (10%) was added to stabilize the receptor andaliquots were stored at −80° C.

[0144] For binding to PPARγ, an aliquot of receptor was incubated inTEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mLβ-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mLaprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamidine and 0.5 mM PMSF)containing 0.1% non-fat dry milk and 10 nM [³H₂] AD5075, (21 Ci/mmole),±test compound as described in Berger et al., Novel peroxisomeproliferator-activated receptor (PPARγ) and PPARδ ligands producedistinct biological effects, J. Biol. Chem. (1999), 274, 6718-6725.)Assays were incubated for ˜16 hr at 4° C. in a final volume of 150 μL.Unbound ligand was removed by incubation with 100 μLdextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

[0145] For binding to PPARδ, an aliquot of receptor was incubated inTEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mLβ-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mLaprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamide and 0.5 mM PMSF)containing 0.1 % non-fat dry milk and 2.5 nM [³H₂]3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylaceticacid (17 Ci/mmole), ± test compound as described in Berger et al., Novelperoxisome proliferator-activated receptor (PPARγ) and PPARδ ligandsproduce distinct biological effects, J. Biol. Chem. (1999), 274,6718-6725). [³H₂]3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4,5-isoxazoloxy)propylthio)phenylaceticacid as a non-labelled compound is taught in Ex. 20 of WO 97/28137.Assays were incubated for ˜16 hr at 4° C. in a final volume of 150 μL.Unbound ligand was removed by incubation with 100 μLdextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

[0146] For binding to PPARα, an aliquot of receptor was incubated inTEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mLβ-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mLaprotinin, 2 μg/mL leupeptin, 2 μg/mL benzamide and 0.5 mM PMSF)containing 0.1% non-fat dry milk and 5.0 nM[³H₂](3-(4-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)butyloxy))phenylaceticacid (34 Ci/mmole), ± test compound. This is a tritium labelled variantof Ex.62 in WO 97/28137. Assays were incubated for ˜16 hr at 4° C. in afinal volume of 150 μL. Unbound ligand was removed by incubation with100 μL dextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

[0147] B). Gal-4 hPPAR Transactivation Assays

[0148] The chimeric receptor expression constructs, pcDNA3-hPPARγ/GAL4,pcDNA3-hPPARδ/GAL4, pcDNA3-hPPARα/GAL4 were prepared by inserting theyeast GAL4 transcription factor DBD adjacent to the ligand bindingdomains (LBDs) of hPPARγ, hPPARδ, hPPARζ, respectively. The reporterconstruct, pUAS(5×)-tk-luc was generated by inserting 5 copies of theGAL4 response element upstream of the herpes virus minimal thymidinekinase promoter and the luciferase reporter gene. pCMV-lacZ contains thegalactosidase Z gene under the regulation of the cytomegaloviruspromoter. COS-1 cells were seeded at 12×10³ cells/well in 96 well cellculture plates in high glucose Dulbecco's modified Eagle medium (DMEM)containing 10% charcoal stripped fetal calf serum (Gemini Bio-Products,Calabasas, Calif.), nonessential amino acids, 100 units/ml Penicillin Gand 100 mg/ml Streptomycin sulfate at 37 ° C. in a humidified atmosphereof 10% CO₂. After 24 h, transfections were performed with Lipofectamine(GIBCO BRL, Gaithersburg, Md.) according to the instructions of themanufacturer. Briefly, transfection mixes for each well contained 0.48μl of Lipofectamine, 0.00075 μg of pcDNA3-PPAR/GAL4 expression vector,0.045 μg of pUAS(5×)-tk-luc reporter vector and 0.0002 tμof pCMV-lacZ asan internal control for transactivation efficiency. Cells were incubatedin the transfection mixture for 5 h at 37° C. in an atmosphere of 10%CO₂. The cells were then incubated for ˜48 h in fresh high glucose DMEMcontaining 5% charcoal stripped fetal calf serum, nonessential aminoacids, 100 units/ml Penicillin G and 100 mg/ml Streptomycinsulfate±increasing concentrations of test compound. Since the compoundswere solubilized in DMSO, control cells were incubated with equivalentconcentrations of DMSO; final DMSO concentrations were ≦0.1%, aconcentration which was shown not to effect transactivation activity.Cell lysates were produced using Reporter Lysis Buffer (Promega,Madison, Wis.) according to the manufacturer's instructions. Luciferaseactivity in cell extracts was determined using Luciferase Assay Buffer(Promega, Madison, Wis.) in an ML3000 luminometer (DynatechLaboratories, Chantilly, Va.). β-galactosidase activity was determinedusing β-D-galactopyranoside (Calbiochem, San Diego, Calif.).

[0149] Measurement of Antagonism/Partial Agonism

[0150] Antagonists and partial agonists are well known in the art. Theabove assays can be used to measure the PPARγ antagonism/partial agonismof the compounds disclosed herein or of other compounds by measuring thePPARγ agonism of a “full” agonist and then measuring the inhibition(usually as a % inhibition) of the full PPARγ agonist when a sample ofthe compound being tested is also included in the assay. A full agonistis a PPARγ agonist that is known to be very effective in comparison withother PPARγ agonists. Examples of full agonists include rosiglitazone,pioglitazone and3-chloro-4-(3-(3-phenyl-7-propylbenzofuran-6-yloxy)propylthio)phenylaceticacid (described by Berger et al, Journal of Biological Chemistry Vol274, 6718-6725, 1999). The synthesis of3-chloro-4-(3-(3-phenyl-7-propylbenzofuran-6-yloxy)propylthio)phenylaceticacid is disclosed in U.S. Pat. No. 5,859,051.

[0151] Compounds that are PPARγ antagonists or partial agonists and thatmay be useful in treating obesity and possibly other conditions that aremodulated by PPARγ are expected to inhibit the PPARγ agonism of a fullPPARγ agonist to a level of less than 50% of its normal level of agonismusing the GAL4 chimeric receptor transcriptional assay, and possiblyless than 25% of its normal level of agonism.

[0152] A second assay method that can also be used is the PPAR-CBP HTRFassay, described by Zhou, et al, Molecular Endocrinology, Vol. 12,1594-1604 (1998), which reference is incorporated herein by reference. Athird assay method that can be used is the 3T3-L1 pre-adipocytedifferentiation assay, described by Berger et al, Journal of BiologicalChemistry, Vol 274, 6718-6725 (1999). These assays are summarized below.

[0153] PPAR-CBP HTRF Assay

[0154] Briefly, 100 mM HEPES, 123 mM KF, 0.125% (wt/vol) CHAPS, 0.05%dry milk, 1 nM GST-PPARγ LBD, 2 nM anti-GST-(Eu)K, 10 nMbiotin-CBP₁₋₄₅₃, 20 nM SA/XL665, a potent PPARγ agonist, and thecompound being tested (100 nM) at several concentrations are incubatedovernight at 4° C. Fluorescence is then read on a Discovery instrument(Packard). Data are expressed as the ratio, multiplied by a factor of10⁴, of the emission intensity at 665 nM to that at 620 nM.

[0155] 3T3-L1 Preadipocyte Differentiation Assay

[0156] 3T3-L1 cells are obtained from American Type Culture Collection.Passage numbers 3 to 9 are used. Monolayer fibroblasts are maintained inmedium A (Dulbecco's modified Eagle's medium with 10% fetal calf serum,100 units/ml penicillin, and 100 μg/ml streptomycin) at 37° C. in 5%CO₂. For experiments, the cells are incubated with medium A(supplemented with 150 nM insulin, 1 μM dexamethasone) in the presenceof 100 nM rosiglitazone and various concentrations of test compound for5 days (with one medium change). Total RNA is prepared using Ultraspec™RNA isolation system (Biotecx, Houston, Tex.). RNA concentration isquantitated by absorbance at 260 nm. Equal amounts of RNA samples aredenatured in formamide/formaldehyde and applied to Hybond™-N membranes(Amersham) using a slot blot apparatus (BioRad). Prehybridization isperformed at 42° C. for 1-3 h in 40-50% formamide in a solutioncontaining 25 mM sodium phosphate, pH 7.4, 0.9 M sodium chloride, 50 mMsodium citrate, 0.1% each of gelatin, ficoll, and polyvinylpyrollidone,0.5 % SDS, and 100 μg/ml denatured salmon sperm DNA. Hybridization iscarried out at the same temperature for 20 h in the same solution with³²P-labeled aP2 cDNA probe (2×10⁶ cpm/ml). After washing the membranesunder appropriately stringent conditions, the hybridization signals areanalyzed with a Phosphorlmager (Molecular Dynamics).

SYNTHETIC METHODS AND EXAMPLES

[0157] The following Examples are provided to illustrate the invention,including methods of making the compounds of the invention, and are notto be construed as limiting the invention in any manner. The meanings ofthe substituent groups X, Y, Z, R and R₁ in the following schemes can bedetermined by comparison of the schemes with Examples 1-20.

EXAMPLES Example 1

[0158]

[0159]N-benzyl-N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}amine(1): {4-[(benzylamino)methyl]cyclohexyl}methanol (CAS 46843-17-8) (594mg, 2.55 mmole, 1.0 eq) was dissolved in 2 mL of N,N-dimethylfornamide,then treated with imidazole (434 mg, 6.1 mmole, 2.5 eq) anddimethyl-tert-butylsilyl chloride (461 mg, 3.06 mmole, 1.2 eq). Thesolution was stirred for 18 hours, then it was diluted withdichloromethane and washed 3× with water. The organic was dried overpotassium carbonate, filtered and evaporated. The crude isolate waspurified by silica gel chromatography to give the TBS protected alcohol(1) in quantitative yield. Mass spectrum (ES+), calculated M+347.26,observed (M+1) 348.3.

[0160]N-benzyl-N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}sulfamide(2): (1)(880 mg, 2.53 mmole, 1.0 eq) was dissolved in 20 mL of1,2-dimethoxyethane. Sulfamide (1.22 grams, 12.66 mmole, 5.0 eq) wasadded and the reaction was stirred at reflux overnight. Monitoring byTLC shows that the reaction is complete, so the 1,2-dimethoxyethane wasevaporated and the crude reconstituted in dichloromethane. The organiclayer was washed with water, dried, filtered and evaporated to give thetarget compound in 88% yield. Mass spectrum (ES+), calculated M+426.69,observed (M+1) 427.3.

[0161]N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]-N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}sulfamide (3): Intermediate 2 (914 mg, 2.14 mmole, 1.0eq) was dissolved in 30 mL of dichloromethane, and dimethylaminopyridine(288 mg, 2.36 mmole, 1.1 eq), N-methylmorpholine (0.26 mL, 2.36 mmole,1.1 eq), and 3,5-bis(trifluoromethyl)benzoyl chloride (0.39 mL, 2.14mmole, 1.0 eq) was stirred at room temperature for 24 hours. Thereaction mixture was then diluted with dichloromethane, washed with 1Nhydrochloric acid, dried over sodium sulfate, filtered and evaporated.Crude was dissolved in petroleum ether, product precipitates outcleanly. Yield of target compound 50%. NMR 300 Mz δ 0.0 (S,6H), 0.87 (s,9H), 0-68-1.0 (m, 4H), 1.23-1.55 (m, 2H), 1.76 (Br d, 4H, J=12 Hz), 3.35(d, 2H, J=7.5 Hz), 3.42 (d, 2H, J=7.5 Hz), 4.58 (s, 2H), 7.13-7.39(mult, 6H), 8.09 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 8.9 (s, 1H).

[0162]N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]-N-{[4-(hydroxymethyl)cyclohexyl]methyl}sulfamide(4): Silyl ether (3) (49 mg, 73 μmole, 1.0 eq) was dissolved in 3.5 mlof acetic acid/water/tetrahydrofuran in a 4/2/1 v/v ratio and stirred atroom temperature overnight. The reaction mixture was diluted with waterand ethyl acetate. The water layer was extracted 3× with ethyl acetateand the organic then washed 3× with water. The organic layer was driedover sodium sulfate, filtered and evaporated to give the target compoundin 75% yield. Mass spectrum (ES+), calculated M+552.15, observed (M+1)553.2.

[0163](4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylbenzoate (5): Alcohol (6) (80 mg, 140 μmole, 1.0 eq) was suspended indichloromethane (0.7 ml) and triethylamine (49 μL, 350 μmole 2.5 eq) andbenzoyl chloride (20 μL, 168 μmole, 1.2 eq) were added. The reaction wasstirred at room temperature overnight, then purified directly by silicagel chromatography to give the title compound. Mass spectrum (ES+),calculated M+656, observed (M+1) 657.

Example 2

[0164]

[0165](4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylpentanoate (6): Following procedure to make (5), valeryl chloride wassubstituted for benzoyl chloride to give the title compound afterpurification. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.14 (s, 1H),7.36 (d, 2H), 7.25 (t, 2H), 7.17 (t, 1H), 4.38 (s, 2H), 3.70 (d, 2H),3.30 (water), 2.917 (d, 2H), 2.48 (DMSO), 2.22 (t, 2H), 1.62 (m, 2H),1.52 (m, 2H), 1.45 (m, 2H), 1.37 (m, 1H), 1.26 (m, 1H), 1.22 (m, 2H),0.82 (t, 3H), 0.63 (m, 4H).

Example 3

[0166]

[0167](4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylphenylcarbamate (7): Intermediate (4) (80 mg, 140 μmole, 1.0 eq) wasdissolved in acetonitrile (10 mL) and phenyl isocyanate (18 μL, 168μmole, 1.2 eq) was added. The mixture was refluxed for 24 hours, thendiluted with water and extracted repeatedly with dichloromethane.Reconstituted in dichloromethane, filtered off precipitate and purifiedmaterial isolated from filtrate by RP-HPLC to give title compound. ¹HNMR (400 MHz, MeOH-d4): δ 0-75-9.0 (m, 4H), 1.38-1.60(m, 2H), 1.68-1.84(m, 4H), 3.21 (d, 2H, J=8 Hz), 3.86 (d, 2H, J=8 Hz), 4.51 (s, 2H), 7.0(t, 1H, J=8 Hz) 7.17-7.30 (mult, 5H), 7.33-7.7.45 (mult, 4H), 8.11 (s,1H), 8.42 (s, 2H).

Example 4

[0168]

[0169](4-{[({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylphenylcarbamate (8): 7 (31.5 mg, 47 mmole, 1.0 eq) was dissolved in 4/1methanol/ethyl acetate (1.25 mL) and 15 mg of 20% palladium hydroxide oncarbon (wet) was added. The vessel was evacuated and charged withhydrogen and stirred overnight. The catalyst was fitered over celite andthe filtrate evaporated to give the title compound in nearlyquantitative yield. ¹H NMR (500 MHz, DMSO-d6): δ 12.23 (br s, 1H), 9.54(s, 1H), 8.50 (s, 2H), 8.28 (s, 1H), 7.42 (d, 2H), 7.24 (t, 2H), 6.95(t, 1H), 3.84 (d, 2H), 2.70 (br s, 2H), 1.54-1.38 (m, 2H), 0.88 (m, 4H).

Example 5

[0170]

[0171](4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylbenzylcarbamate (9): Following procedure to make (5), benzyl isocyanatewas substituted for benzoyl chloride to give the title compound afterpurification. ¹H NMR: (500 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.45 (s, 2H),8.31 (s, 1H), 7.58 (t, 1H), 7.35 (d, 2H), 7.27 (t, 4H), 7.19 (t, 3H),4.48 (s, 2H), 4.13 (d, 2H), 3.68 (d, 2H), 3.3 (water), 3.12 (d, 2H),2.48 (DMSO), 1.62 (m, 4H), 1.45 (m, 1H), 1.37 (m, 1H), 0.63 (m, 4H).

Example 6

[0172]

[0173] (4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl 2-phenylethylcarbamate (10):Following procedure to make (9), phenethyl isocyanate was substitutedfor benzyl isocyanate to give the title compound after purification. ¹HNMR (500 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.45 (s, 2H), 8.10 (s, 1H),7.37 (d, 2H), 7.27 (t, 3H), 7.16 (m, 3H), 7.07 (t, 2H), 4.34 (s, 2H),3.61 (d, 2H), 3.14 (m, 2H), 3.30 (water), 2.88 (d, 2H), 2.66 (t, 2H),2.48 (DMSO), 1.62 (m, 2H), 1.52 (m, 2H), 1.32 (m, 1H), 1.26 (m, 1H),0.63 (m, 4H).

Example 7

[0174]

[0175] (4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino }sulfonyl)amino]methyl }cyclohexyl)methyl 3-methoxyphenylcarbamate (11):Following procedure to make (9), 3-methoxyphenyl isocyanate wassubstituted for benzyl isocyanate and diisopropylethylamine substitutedfor triethylamine to give the title compound after purification. ¹H NMR(500 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.45 (s, 2H), 8.10 (s, 1H), 7.38 (d,2H), 7.24 (t, 2H), 7.14 (m, 3H), 6.96 (d, 1H), 6.52 (d, 1H), 4.35 (s,2H), 3.75 (d, 2H), 3.68 (s, 3H), 3.30 (water), 2.89 (d, 2H), 2.48(DMSO), 1.63 (m, 4H), 1.42 (m, 1H), 1.29 (m, 1H), 0.66 (m, 4H).

Example 8

[0176]

[0177]N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]-N-({4-[({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)methyl]cyclohexyl}methyl)sulfamide(12): Intermediate (4) (110 mg, 200 μmole, 1.0 eq) was dissolved inacetonitrile, after which triethylamine (84 μL, 600 μmole, 3.0 eq) anddisuccinimidyl carbonate (77 mg, 300 μmole, 1.5 eq) were added and themixture stirred overnight. TLC showed reaction was complete, so it wasdiluted with ethyl acetate and washed twice with 5% aqueous sodiumbicarbonate and once with brine to give the target compound in 97%yield. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.10 (s, 1H), 7.37 (d,2H), 7.25 (t, 2H), 7.17 (t, 1H), 4.34 (s, 2H), 4.04 (d, 2H), 3.30(water), 2.89 (d, 2H), 2.77 (s, 4H), 2.48 (DMSO), 1.65 (m, 2H), 1.54 (m,2H), 1.51 (m, 1H), 1.26 (m, 1H), 0.65 (m, 4H).

[0178](4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylbutylcarbamate (13): N-butyl amine (6 μL, 60 μmole, 1.2 eq) andtriethylamine (10.5 μL, 75 μmole, 1.5 eq) were dissolved indichloromethane (125 μL), then a solution of (12) (34.7 mg, 50 μmole,1.0 eq) in dichloromethane (250 μL) was added to the stirring amines.The reaction was stirred overnight, then purified directly by silica gelchromatography to give the title compound in 89% yield. ¹H NMR (500 MHz,DMSO-d6): δ 8.45 (s, 2H), 8.11 (s, 1H), 7.36 (d, 2H), 7.24 (t, 2H), 7.17(t, 1H), 6.95 (t, 1H), 4.35 (s, 2H), 3.61 (d, 2H), 3.30 (water), 2.89(d, 4H), 2.48 (DMSO), 1.61 (m, 2H), 1.54 (m, 2H), 1.34-1.19 (m, 6H),0.82 (t, 3H), 0.61 (m, 4H).

Example 9

[0179]

[0180](4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl1-methylbutylcarbamate (14): Following the procedure to make (13),1-methylbutyl amine was substituted for butyl amine to give the titlecompound after purification. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H),8.12 (s, 1H), 7.37 (d, 2H), 7.24 (t, 2H), 7.17 (t, 1H), 6.79 (d, 1H),4.35 (s, 2H), 3.60 (d, 2H), 3.41 (m, 1H), 3.30 (water), 2.89 (d, 2H),2.48 (DMSO), 1.62 (m, 2H), 1.55 (m, 2H), 1.34-1.19 (m, 6H), 0.96 (d,3H), 0.80 (t, 3H), 0.62 (m, 4H).

Example 10

[0181]

[0182]N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]-N-({4-[(pentyloxy)methyl]cyclohexyl}methyl)sulfamide(15): Intermediate (4) (27.6 mg, 50 μmole, 1.0 eq) was dissolved indichloromethane (250 μL), after which 2,6-di-t-butyl pyridine (36 μL,160 μmole, 3.2 eq), silver triflate (38.5 mg, 150 μmole, 3.0 eq) andiodopentane (23 μL, 175 μmole, 3.5 eq) were added. After 45 minutes thereaction mixture was directly purified to give 23 mg of the titlecompound. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.15 (s, 1H), 7.36(d, 2H), 7.24 (t, 2H), 7.17 (t, 1H), 4.39 (s, 2H), 3.30 (water), 3.23(t, 2H), 3.01 (d, 2H), 2.92 (d, 2H), 2.48 (DMSO), 1.61 (m, 2H), 1.54 (m,2H), 1.41 (m, 2H), 1.34-1.19 (m, 6H), 0.82 (t, 3H), 0.62 (m, 4H).

Example 11

[0183]

[0184] Ethyl4-{[(aminosulfonyl)(benzyl)amino]methyl}cyclohexanecarboxylate (16): Thehydrochloride salt of trans 4-[benzylamino]methyl]cyclohexane carboxylicacid ethyl ester (CAS 140406-44-6) (275 mg, 0.88 mmole, 1.0 eq) wassuspended in 1,2-dimethoxyethane. Triethylamine (139 μL, 1.0 mmole, 1.13eq) and sulfamide (481 mg, 5.0 mmole, 5.67 eq) were added and themixture was heated to reflux overnight. DME was evaporated and the crudereconstituted in ethyl acetate, then washed with water. The organic wasdried over sodium sulfate, filtered and evaporated. NMR confirmsformation of title compound. ¹H NMR (500 MHz, DMSO-d6): δ 7.40-7.20 (m,5H), 6.79 (s, 2H), 4.18 (s, 2H), 3.99 (m, 2H), 2.81 (d, 2H), 2.08 (m,1H). 1.74 (m, 2H), 1.61 (m, 2H), 1.25 (m, 1H), 1.12 (t, 3H), 1.02 (dq,2H), 0.68 (dq, 2H).

[0185] Ethyl 4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino }sulfonyl)amino]methyl}cyclohexanecarboxylate (17): A solution of (16)(250 mg, 0.71 mmole, 1.0 eq), dimethyaminopyridine (129 mg, 1.06 mmole,1.5 eq) and 3,5-bis(trifluoromethyl)benzoyl chloride (141 μL, 0.78mmole, 1.1 eq) in dichloromethane (5 mL) was stirred overnight. Themixture was diluted further with dichloromethane, washed twice withdilute hydrochloric acid and twice with 5% aqueous sodium bicarbonate.The organic was dried over sodium sulfate, filtered and evaporated andthe crude purified by silica gel chromatography to give >85% pure titlecompound. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.29 (s, 1H),7.40-7.20 (m, 5H), 4.46 (s, 2H), 3.98 (m, 2H), 3.09 (d, 2H), 2.09 (m,1H), 1.74 (m, 2H), 1.61 (m, 2H), 1.25 (m, 1H), 1.11 (t, 3H), 1.02 (dq,2H), 0.68 (dq, 2H).

[0186] 4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexanecarboxylic acid (18): Intermediate(17) (30 mg, 50 mmole, 1.0 eq) was dissolved in methanol (0.5 mL) and0.5 N sodium hydroxide was added (0.23 mL, 115 mmole, 2.3 eq). Thehydrolysis reaction was heated to 40° C. for 2 hours, at which pointhydrolysis was complete. The reaction mixture was diluted with water,acidified with dilute hydrochloric acid and extracted with ethylacetate. The organic was dried over sodium sulfate, filtered andevaporated to give the title compound in nearly quantitative yield. ¹HNMR (500 MHz, DMSO-d6): δ 12.47 (s, 1H), 11.93 (s, 1H), 8.45 (s, 2H),8.39 (s, 1H), 7.40-7.20 (m, SH), 4.52 (s, 2H), 3.21 (d, 2H), 2.09 (m,1H), 1.76 (m, 2H), 1.61 (m, 2H), 1.33 (m, 1H), 1.02 (m, 2H), 0.80 (m,2H).

[0187]N-benzyl-4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexanecarboxamide (19): Carboxylic acid (18) (27 mg, 48 μmole, 1.0 eq) wasdissolved in dichloromethane (250 μL), treated with1-hydroxybenzotriazole (7.7 mg, 57 μmole, 1.2 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11 mg, 57μmole, 1.2 eq) and benzylamine (5.7 μL, 52 μmole, 1.1 eq) and stirredfor 96 hours.

[0188] Diluted with dichloromethane, then washed with dilute sodiumbicarbonate and dilute hydrochloric acid. The organic layer was driedover sodium sulfate, filtered and evaporated and the crude purified bysilica gel chromatography to give the title compound. ¹H NMR (500 MHz,DMSO-d6): δ 8.45 (s, 2H), 8.16 (s, 1H), 8.13 (t, 1H), 7.40-7.20 (m, 9H),4.37 (s, 2H), 4.17 (d, 2H), 2.96 (d, 2H), 1.98 (m, 1H), 1.63 (m, 4H),1.22 (m, 1H), 1.06 (m, 2H), 0.66 (m, 2H).

Example 12

[0189]

[0190](4-{[Benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylmethanesulfonate (20): Intermediate (4) (275 mg, 0.50 mmole, 1.0 eq) wasdissolved in dichloromethane (2.5 mL), then treated with triethylamine(175 μL, 1.25 mmole, 2.5 eq) and methanesulfonyl chloride (43 μL, 0.55mmole, 1.1 eq). The reaction was stirred overnight, then diluted withdichloromethane, washed with 5% aqueous citric acid followed by water,dried over sodium sulfate, filtered and evaporated to give the titlecompound in 91% yield. ¹H NMR (500 MHz, DMSO-d6): δ 12.47 (s, 1H), 8.45(s, 2H), 8.40 (s, 1H), 7.34 (d, 2H), 7.26 (t, 2H), 7.20 (m, 2H), 4.53(s, 2H), 3.92 (d, 2H), 3.30 (water), 3.22 (d, 2H), 3.10 (s, 3H), 2.48(DMSO), 1.63 (m, 4H), 1.53 (m, 1H), 1.37 (m, 1H), 0.77 (m, 4H).

[0191]N-{[4-(azidomethyl)cyclohexyl]methyl}-N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]sulfamide(21): Mesylate (20) (283 mg, 0.45 mmole, 1.0 eq) was dissolved inN,N-dimethylformamide (3 mL) and sodium azide (292 mg, 4.5 mmole, 10.0eq) was added. CAUTION: SODIUM AZIDE IS EXPLOSIVE. The reaction washeated to 90° C. overnight. The reaction mixture was then diluted withethyl acetate and washed twice with water and 3× with brine. The organicwas dried over sodium sulfate, filtered and evaporated to give the titlecompound in nearly quantitative yield. ¹H NMR (500 MHz, DMSO-d6): δ12.47 (s, 1H), 8.45 (s, 2H), 8.17 (s, 1H), 7.36 (d, 2H), 7.25 (t, 2H),7.18 (m, 2H), 4.39 (s, 2H), 3.30 (water), 3.08(d, 2H), 2.96 (d, 2H),2.48 (DMSO), 1.60 (m, 4H), 1.22 (m, 2H), 0.65 (m, 4H).

[0192]N-{[4-(aminomethyl)cyclohexyl]methyl}-N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]sulfamide(22): Azide (21) (254 mg, 0.44 mmole, 1.0 eq) was dissolved in methanol(2.2 mL), then the vessel was evacuated and charged with nitrogen. 10%Palladium on carbon (93 mg, 88 μmole, 0.2 eq) was added to the reaction,then the vessel was evacuated and charged with hydrogen gas. Reactionwas deemed complete at 4.5 hours. Catalyst was filtered off over a padof celite and the filtrate was evaporated. The crude product wasreconstituted in 1,4-dioxane, then 4N hydrogen chloride in dioxane (180μL, 720 μmole, 1.6 eq) was added and the solution diluted with etheruntil the amine hydrochloride salt precipitated out. This was filtered,then the filtrate was evaporated and taken up in 1 ml dioxane. It wasdiluted again with ether, and a second crop of the amine hydrochloridewas obtained. ¹H NMR (500 MHz, DMSO-d6): δ 12.49 (s, 1H), 8.46 (s, 2H),8.40 (s, 1H), 7.89 (s, 3H), 7.35 (d, 2H), 7.26 (t, 2H), 7.19 (m, 2H),4.52 (s, 2H), 3.30 (water), 3.23 (d, 2H), 2.53 (t, 2H), 2.48 (DMSO),1.65 (m, 4H), 1.38 (m, 2H), 0.71 (m, 4H).

[0193]N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]-N′-phenylurea(23): Amine (22) (25.2 mg, 46 μmole, 1.0 eq) was suspended indichloromethane, then triethylamnine (16 μL, 114 μmole, 2.5 eq) andphenyl isocyanate (6 μL, 55 μmole, 1.2 eq) were added and the reactionstirred overnight. Silica gel chromatography provided the titlecompound. ¹H NMR (500 MHz, DMSO-d6): δ 12.46 (s, 1H), 8.45 (s, 2H), 8.27(s, 1H), 8.23 (s, 1H), 7.36 (d, 2H), 7.32 (d, 2H), 7.25 (t, 2H), 7.18(m, 4H), 6.84 (t, 1H), 6.05 (t, 1H), 4.43 (s, 2H), 3.30 (water), 3.03(s, 2H), 2.81 (t, 2H), 2.48 (DMSO), 1.60 (m, 4H), 1.30 (m, 1H), 1.21 (m,1H), 0.64 (m, 4H).

Example 13

[0194]

[0195]N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]pentanamide(24): Amine (22) (23.5 mg, 40 μmole, 1.0 eq) was suspended indichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) andvaleryl chloride (5 μL, 42 μmole, 1.05 eq) were added and the reactionstirred 30 minutes. Silica gel chromatography provided the titlecompound. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.21 (s, 1H), 7.62(t, 1H), 7.36 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 4.42 (s, 2H), 3.30(water), 3.00 (s, 2H), 2.74 (t, 2H), 2.48 (DMSO), 1.99 (t, 2H), 1.56 (m,4H), 1.41 (m, 2H), 1.26 (m, 1H), 1.20 (m, 3H), 0.81 (t, 3H), 0.60 (m,4H).

Example 14

[0196]

[0197]N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]benzamide(25): Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended indichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) andbenzoyl chloride (4.7 μL, 40 μmole, 1.0 eq) were added and the reactionstirred 30 minutes. Silica gel chromatography provided the titlecompound. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.32 (t, 1H), 8.18(s, 1H), 7.77 (d, 2H), 7.47 (t, 1H), 7.37 (m, 4H), 7.25 (d, 2H), 7.18(t, 1H), 4.40 (s, 2H), 3.30 (water), 2.98 (t, 4H), 2.48 (DMSO), 1.61 (m,4H), 1.36 (m, 1H), 1.28 (m, 1H), 0.62 (m, 4H).

Example 15

[0198]

[0199]N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]-N′-butylurea(26): Amine (22) (35.3 mg, 60 μmole, 1.0 eq) was suspended indichloromethane, then triethylamine (25 μL, 180 μmole, 3.0 eq) anddisuccinimidyl chloride (19.2 mg, 75 μmole, 1.25 eq) were mixed togetherand the reaction stirred for 15 minutes. n-Butyl amine (7.4 μL, 75μmole, 1.25 eq) was then added and the reaction stirred overnight. Themixture was then purified directly by silica gel chromatography to givethe title compound. ¹H NMR (500 MHz, DMSO-d6): δ 8.45 (s, 2H), 8.18 (s,1H), 7.37 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 5.66 (t, 1H), 4.39 (s,2H), 3.30 (water), 2.95 (d, 2H), 2.91 (q, 2H), 2.69 (t, 2H), 2.48(DMSO), 1.56 (m, 4H), 1.25 (m, 5H), 1.10 (m, 1H), 0.83 (t, 3H), 0.57 (m,4H).

Example 16

[0200]

[0201] Butyl(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methylcarbamate (27): Amine (22) (60.4 mg, 103 μmole, 1.0 eq) was suspended indichloromethane, then triethylamine (35.8 μL, 257 μmole, 2.5 eq) andn-butyl chloroformate (13.7 μL, 108 μmole, 1.05 eq) were added and thereaction stirred 4 hours. Silica gel chromatography provided the titlecompound. ¹H NMR (500 MHz, DMSO-d6): δ 12.46 (s, 1H), 8.45 (s, 2H), 8.34(s, 1H), 7.34 (d, 2H), 7.26 (t, 2H), 7.19 (t, 1H), 6.96 (t, 1H), 4.50(s, 2H), 3.87 (t, 2H), 3.30 (water), 3.13 (d, 2H), 2.70 (t, 2H), 2.48(DMSO), 1.57 (m, 4H), 1.46 (m, 2H), 1.29 (m, 3H), 1.19 (m, 1H), 0.85 (t,3H), 0.69 (m, 2H), 0.57 (m, 2H).

Example 17

[0202]

[0203]N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}cyclohexyl)methyl]benzenesulfonamide(28): Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended indichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) andbenzenesulfonylchloride (5.4 μL, 42 μmole, 1.05 eq) were added and thereaction stirred 30 minutes. Silica gel chromatography provided thetitle compound. ¹H NMR (500 MHz, DMSO-d6): δ 8.44 (s, 2H), 8.17 (t, 1H),7.72 (dd, 2H), 7.55 (m, 4H), 7.35 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H),4.37 (s, 2H), 3.30 (water), 2.93 (t, 2H), 2.48 (DMSO), 2.44 (t, 2H),1.61 (m, 4H), 1.21 (m, 1H), 1.11 (m, 1H), 0.51 (m, 4H).

Example 18

[0204]

[0205] Ethyl 4-[(acetylamino)methyl]cyclohexanecarboxylate (29): trans4-(Aminomethyl)cyclohexane carboxylic acid ethyl ester (CAS 35879-53-9)(222 mg, 1.0 mmole, 1.0 eq) was dissolved in dichloromethane (5 mL) andtriethyl amine (0.35 mL, 2.5 mmole, 2.5 eq) and acetic anhydride (143μL, 1.50 mmole, 1.5 eq) was added. The reaction was stirred overnightand was complete in 18 hours. The reaction was diluted withdichloromethane and washed twice with dilute aqueous hydrochloric acid.The organic was dried over sodium sulfate, filtered and evaporated togive the title compound in quantitative yield. ¹H NMR (500 MHz,DMSO-d6): δ 7.76 (s, 1H), 4.01 (q, 2H), 2.85 (t, 2H), 2.17 (m, 1H), 1.86(m, 2H), 1.77 (s, 3H), 1.69 (m, 2H), 1.24 (m, 3H), 1.13 (t, 3H), 0.88(m, 2H).

[0206] N-{[4-(hydroxymethyl)cyclohexyl]methyl}acetamide (30): Ester (29)(220 mg, 0.97 mmole, 1.0 eq) was dissolved in tetrahydrofuran, thenlithium aluminum hydride (81 mg, 2.14 mmole, 2.2 eq) was added and thereaction stirred. This was worked up after 90 minutes by quenching viasimultaneous addition of water and 2N sodium hydroxide. The aqueousmixture was extracted with ethyl acetate to give the alcohol titlecompound in 87% yield. ¹H NMR (500 MHz, DMSO-d6): δ 7.74 (s, 1H), 4.31(t, 1H), 3.17 (t, 2H), 2.84 (t, 2H), 1.77 (s, 3H), 1.69 (m, 4H), 1.25(m, 2H), 0.81 (m, 4H).

[0207]N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}acetamide(31): Primary alcohol (30) was treated with t-butyldimethysilyl chlorideand triethylamine in dichloromethane to give title compound in similarfashion to procedure used to make (1). ¹H NMR (500 MHz, DMSO-d6): δ 7.74(s, 1H), 3.35 (d, 2H), 2.84 (t, 2H), 1.77 (s, 3H), 1.68 (m, 4H), 1.28(m, 2H), 0.84 (m, 13H), 0.00 (s, 6H).

[0208]N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}-N-ethylamine(32): Intermediate (31) (50 mg, 168 mmole, 1.0 eq) was dissolved intetrahydrofuran (0.5 mL) and lithium aluminum hydride (16.4 mg, 432mmole, 2.6 eq) was added. Heated to reflux for 24 hours at which pointreaction was complete. Cooled, quenched with saturated Rochelle's salt,extracted twice with ethyl acetate, dried, filtered and evaporatedfiltrate to give crude title compound. ¹H NMR (500 MHz, DMSO-d6): δ 3.35(d, 2H), 2.45 (m, 2H), 2.29 (d, 2H), 1.72 (m, 4H), 1.28 (m, 2H), 0.96(t, 3H), 0.84 (m, 13H), 0.00 (s, 6H).

[0209]N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}-N-ethylsulfamide(33): Following the procedure to make (16), (32) was treated withsulfamide and DME at reflux overnight to give the title compound. ¹H NMR(500 MHz, DMSO-d6): δ 6.55 (s, 2H), 3.38 (d, 2H), 3.04 (m, 2H), 2.77 (d,2H), 1.72 (m, 4H), 1.44 (m, 1H), 1.32 (m, 1H), 1.06 (t, 3H), 0.84 (m,13H), 0.00 (s, 6H).

[0210]N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}-N-ethylsulfamide(34): Following the procedure to make (17), intermediate (33) was usedin place of (16) to give the title compound. ¹H NMR (500 MHz, DMSO-d6):δ 8.53 (s, 2H), 8.42 (s, 1H), 3.35 (m, 4H), 3.15 (d, 2H), 1.70 (m, 4H),1.51 (m, 1H), 1.32 (m, 1H), 1.08 (t, 3H), 0.83 (m, 13H), 0.00 (s, 6H).

[0211]N′-[3,5-bis(trifluoromethyl)benzoyl]-N-ethyl-N-{[4-(hydroxymethyl)cyclohexyl]methyl}sulfamide(35): Following the procedure to make (4), intermediate (34) wassubstituted for (3) to give the title compound. ¹H NMR (500 MHz,DMSO-d6): δ 8.43 (s, 2H), 8.09 (s, 1H), 4.28 (t, 1H), 3.15 (m, 4H), 2.91(d, 2H), 1.74 (m, 4H), 1.43 (m, 1H), 1.24 (m, 1H), 1.02 (t, 3H), 0.78(m, 4H).

[0212](4-{[({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)(ethyl)amino]methyl}cyclohexyl)methylphenylcarbamate (36): Alcohol (35) (11.6 mg, 24 mmole, 1.0 eq) wasdissolved in dichloromethane followed by the addition of triethylamine(10 mL, 72 mmole, 3.0 eq) and phenyl isocyanate (2.8 mL, 26 mmole, 1.05eq). Added additional triethylamine and phenylisocyanate to drivereaction to completion. Purified by silica gel chromatography to providethe title compound. ¹H NMR (500 MHz, DMSO-d6): δ 12.39 (s, 1H), 9.55 (s,1H), 8.54 (s, 2H), 8.39 (s, 1H), 7.43 (s, 2H), 7.24 (t, 2H), 6.95 (t,1H), 3.88 (d, 2H), 3.35 (q, 2H), 3.19 (d, 2H), 1.77 (m, 4H), 1.57 (m,2H), 1.09 (t, 3H), 0.92 (m, 4H).

Example 19

[0213]

[0214]N-benzyl-N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl}-N′-(3,5-dimethylbenzoyl)sulfamide(37): 3,5-Dimethylbenzoic acid (1.50 g, 10.0 mmole, 1.0 eq) wassuspended in 5 mL dichloromethane and heated to reflux, after which asolution of chlorosulfonyl isocyanate (0.87 mL, 10.0 mmole, 1.0 eq) in 2mL dichloromethane was added. Reaction mixture became clear, andremained so after 40 minutes of reflux. Cooled to room temperature,added hexanes and began to evaporate when solid precipitated out.Recovered filtered solid. 23 mg, 92 μmole, 1.0 eq of this material wasadded to a mixture of intermediate (2) (34 mg, 92 μmole, 1.0 eq) andtriethylamine (39 μL, 277 μmole, 3.0 eq) in dichloromethane (0.5 mL).Reaction was complete at 2 hours, at which point it was purifieddirectly by silica gel chromatography to give the title compound in 86%yield. ¹H NMR (500 MHz, DMSO-d6): δ 11.84 (s, 1H), 7.49 (s, 2H), 7.31(m, 6H), 4.52 (s, 2H), 3.28 (d, 2H), 3.09 (d, 2H), 2.30 (s, 6H), 1.58(m, 4H), 1.31 (m, 1H), 1.22 (m, 1H), 0.82 (s, 9H), 0.66 (m, 4H), 0.04(s, 6H).

[0215]N-benzyl-N′-(3,5-dimethylbenzoyl)-N-{[4-(hydroxymethyl)cyclohexyl]methyl}sulfamide(38): Intermediate (37) was treated as (3) was treated in the synthesisof (4) to give the title alcohol in quantitative yield. ¹H NMR (500 MHz,DMSO-d6): δ 11.85 (s, 1H), 7.50 (s, 2H), 7.31 (m, 6H), 4.52 (s, 2H),4.27 (t, 1H), 3.10 (m, 4H), 2.32 (s, 6H), 1.59 (m, 4H), 1.31 (m, 1H),1.22 (m, 1H), 0.66 (m, 4H).

[0216]{4-[(benzyl{[(3,5-dimethylbenzoyl)amino]sulfonyl}amino)methyl]cyclohexyl}methylphenylcarbamate (39): Alcohol (38) (34.6 mg, 78 mmole, 1.0 eq) in 0.5 mLdichloromethane was treated with triethylamine (38 mL, 272 mmole, 3.5eq) and phenyl isocyanate (17 mL, 156 mmole, 2.0 eq) to give the titlecompound after preparative TLC. ¹H NMR (500 MHz, DMSO-d6): δ 11.85 (s,1H), 9.52 (s, 1H), 7.50 (s, 2H), 7.41 (d, 2H), 7.36 (d, 2H), 7.30 (t,2H), 7.24 (t, 3H), 7.19 (s, 1H), 6.95 (t, 1H), 4.48 (s, 2H), 3.800 (d,2H), 3.07 (d, 2H), 2.32 (s, 6H), 1.64 (m, 4H), 1.47 (m, 1H), 1.34 (m,1H), 0.73 (m, 4H).

Example 20

[0217]

[0218]4-(benzyl-{[(4-t-butylbenzoyl)amino]sulfonyl}aminomethyl)-1-piperidinecarboxylicacid phenylmethyl ester (40):4-[[benzylamino]methyl]-1-piperidinecarboxylic acid phenylmethyl ester(CAS 195314-74-0) was converted to the title compound following theprocedures described to prepare sulfamide (16) and acyl sulfamide (17).

[0219]¹H NMR (CDCl3): δ 8.35 (s, 1H), 7.66 (d, J=8 Hz, 2H), 7.50 (d, J=8Hz, 2H), 7.35 (m, 10H), 5.08 (s, 2H), 4.57 (bs, 2H), 4.08 (m, 2H), 3.36(m, 2H), 2.53 (m, 2H), 1.55 (m, 3H), 1.34 (s, 9H), 1.03 (m, 2H).

What is claimed is:
 1. A compound having the formula I:

including pharmaceutically acceptable salts and prodrugs thereof,wherein X is selected from CH and N; R₁ is—(CH₂)_(a)(Y₁)_(b)(Z)_(c)(Y₂)_(d)R₄; a, b, c, and d are eachindependently 0 or 1, with the proviso that if c is 0, then b and d arenot both 1; Y₁ and Y2 are each independently O or NH; Z is selected fromC(O) and S(O)₂; R₂ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ Cycloalkyl, C₆₋₁₀ Aryl, Heteroaryl, and Heterocycle, andR₂ is optionally substituted with 1-5 groups R₃; Each R₃ isindependently selected from H, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ Aryl, —OC₁₋₆ alkyl, —OC₂₋₆ alkenyl, —OC₂₋₆ alkynyl,—OC₆₋₁₀ Aryl, C₃₋₆ Cycloalkyl, Heteroaryl, Heterocycle, CN, NO₂,S(O)_(m)R₄, SO₂NHR₄, SO₂NR₄R₄, CO₂H, and CONHR₄, wherein each alkyl,alkenyl, alkynyl, Aryl, -Oalkyl, -Oalkenyl, -Oalkynyl, -Oaryl,Cycloalkyl, Heteroaryl, and Heterocycle is optionally substituted with1-5 substituents independently selected from halogen, —OCF₃, —OCH₃, CF₃and CH₃; Each R₄ is independently selected from the group consisting ofH, C₁₋₁₀ alkyl, C₃₋₁₀ Cycloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₆₋₁₀Aryl, Heterocycle, and Heteroaryl, wherein R₄ is optionally substitutedwith 1-3 groups R₅; Each R₅ is independently selected from halogen, C₁₋₆alkyl, C₆₋₁₀ Aryl, —OC₁₆ alkyl, —OC₂₋₆ alkenyl, —OC₂₋₆ alkynyl, —OC₆₋₁₀Aryl, C₃₋₆ Cycloalkyl, CN, NO₂, CO₂H, CO₂C₁-C₆alkyl and CONH₂, whereineach alkyl, Aryl, -Oalkyl, -Oalkenyl, -Oalkynyl, -Oaryl, Cycloalkyl andCO₂alkyl is optionally substituted with 1-5 substituents independentlyselected from halogen, —OCF₃, —OCH₃, CF₃ and CH₃; m is 0, 1 or 2; Eachalkyl, alkenyl and alkynyl group may be linear or branched; Cycloalkylis a saturated or partly saturated monocyclic or bicyclic carbocyclicring system; Aryl is a monocyclic or bicyclic carbocyclic aromatic ringsystem; Heterocycle is a fully saturated or partially saturatedmonocyclic or bicyclic ring system comprising at least one heteroatomselected from N, S and O in the ring and comprising 4 to 11 atoms in thering; and Heteroaryl is a monocyclic or bicyclic aromatic ring systemcomprising at least one ring heteroatom selected from N, O and S andcomprising 4-11 atoms in the ring or rings.
 2. A compound having formulaI as recited in claim 1, wherein X is CH.
 3. A compound having formula Ias recited in claim 2, wherein R₁ is selected from the group consistingof CH₂OCONHR₄, CH₂OCOOR₄, CH₂OCOR₄, CH₂OR₄, CH₂NHCOOR₄, CH₂NHCONHR₄,CH₂NHCOR₄, CH₂NHS(O)₂NHR₄, CH₂NHS(O)₂R₄, CONHR₄, S(O)₂NHR₄, OCONHR₄,NHCOOR₄, NHCONHR₄, NHS(O)₂NHR₄, NHCOR₄, and NHS(O)₂R₄.
 4. A compoundhaving Formula I as recited in claim 2, wherein R1 is selected from thegroup consisting of CH₂OCONHR₄, CH₂OCOOR₄, CH₂OCOR₄, CH₂OR₄, CH₂NHCOOR₄,CH₂NHCONHR₄, CH₂NHCOR₄, CH₂NHS(O)₂NHR₄, and CH₂NHS(O)₂R₄.
 5. A compoundhaving Formula I as recited in claim 1, wherein X is N.
 6. A compoundhaving Formula I as recited in claim 5, wherein R₁ is selected from thegroup consisting of CONHR₄, COOR₄, COR₄, S(O)₂R₄, and S(O)₂NHR₄.
 7. Acompound having Formula I as recited in any of claims 1 to 6, wherein R₂is selected from C₁₋₆ alkyl, CH₂C₃₋₁₀ Cycloalkyl and CH₂C₆₋₁₀ Aryl ,wherein R₂ is optionally substituted with 1-3 halogens, and Cycloalkyland Aryl are optionally substituted with 1-3 groups R₃.
 8. A compoundhaving Formula I as recited in any of claims 1-7, wherein R₂ isCH₂phenyl, where phenyl is optionally substituted with 1-3 groups R₃. 9.A compound having Formula I as recited in any of claims 1-8, whereineach R₃ is independently selected from the group consisting of H,halogen, C₁₋₆ alkyl, and —OC₁₋₆ alkyl, wherein alkyl and -Oalkyl areoptionally substituted with 1-5 fluorine atoms.
 10. A compound havingFormula I as recited in any of claims 1-9, wherein each R₄ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₃₋₆Cycloalkyl, phenyl, and Heteroaryl, wherein Cycloalkyl is a monocycliccarbocyclic ring and Heteroaryl is a monocyclic 5 or 6-membered aromaticring having at least one heteroatom selected from O, S and N in thering, and R₄ is optionally substituted with 1-3 R₅.
 11. A compoundhaving Formula I as recited in any of claims 1-10, wherein R₄ isselected from the group consisting of H, phenyl and C₁₋₆alkyl, whereinphenyl is optionally substituted with 1-3 groups independently selectedfrom halogen, CH₃, CF₃, —OCH₃ and —OCF₃, and alkyl is optionallysubstituted with 1-3 halogens and/or one phenyl, which is optionallysubstituted with 1-3 groups independently selected from halogen, CH₃,CF₃, —OCH₃ and —OCF₃.
 12. A compound having Formula I as recited inclaim 1, wherein: X is selected from CH and N, wherein when X is CH, R₁is selected from the group consisting of CH₂OCONHR₄, CH₂OCOOR₄,CH₂OCOR₄, CH₂OR₄, CH₂NHCOOR₄, CH₂NHCONHR₄, CH₂NHCOR₄, CH₂NHS(O)₂NHR₄,and CH₂NHS(O)₂R₄, and when X is N, R₁ is selected from the groupconsisting of CONHR₄, COOR₄, COR₄, S(O)₂R₄, and S(O)₂NHR₄; R₂ is benzylor C₁₋₆ alkyl, and R₂ is optionally substituted with 1-3 R₃; R₃ isselected from the group consisting of H, halogen, C₁₋₆alkyl, —OCH₃ and—OCF₃ , wherein alkyl is optionally substituted with 1-3 halogens; andEach R₄ is independently selected from the group consisting of H, phenyland C₁₋₆alkyl, wherein phenyl is optionally substituted with 1-3 groupsindependently selected from halogen, CH₃, CF₃, —OCH₃ and —OCF₃, andalkyl is optionally substituted with 1-3 halogens and optionally 1phenyl, which is optionally substituted with 1-3 groups independentlyselected from halogen, CH₃, CF₃, —OCH₃ and —OCF₃.
 13. A compound havingFormula I as recited in claim 12, wherein R₂ is benzyl.
 14. A compoundrepresented by any of the structures of Examples 1-20, shown below,including pharmaceutically acceptable salts and prodrugs thereof:EXAMPLE No. STRUCTURE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20


15. A compound represented by any of the compounds of Examples 1-20, andpharmaceutically acceptable salts and prodrugs thereof, named below: 1.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methylbenzoate; 2.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methylpentanoate; 3.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methylphenylcarbamate; 4.(4-{[({[3,5-bis(trifluoromethyl)benzoyl]amino}-sulfonyl)amino]methyl}cyclohexyl)methylphenylcarcarbamate; 5.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methylbenzylcarbamate; 6.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl2-phenylethylcarbamate; 7.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl3-methoxyphenylcarbamate; 8.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methylbutylcarbamate; 9.(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl1-methylbutylcarbamate; 10.N-benzyl-N′-[3,5-bis(trifluoromethyl)benzoyl]-N-({4-[(pentyloxy)methyl]cyclohexyl}methyl)sulfamide;11.N-benzyl-4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexanecarboxamide; 12.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl]phenylurea;13.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl]pentanamide; 14.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl]benzamide;15.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl]-N′-butylurea;16. Butyl(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methylcarbamate; 17.N-[(4-{[benzyl({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)amino]methyl}-cyclohexyl)methyl]benzenesulfonamide;18.(4-{[({[3,5-bis(trifluoromethyl)benzoyl]amino}sulfonyl)(ethyl)amino]methyl}-cyclohexyl)methylphenylcarbamate; 19.{4-[(benzyl{[(3,5-dimethylbenzoyl)amino]sulfonyl}amino)methyl]cyclohexyl}methyl-phenylcarbamate;and 20.4-(benzyl-{[(4-t-butylbenzoyl)amino]sulfonyl}aminomethyl)-1-piperidinecarboxylicacid phenylmethyl ester.
 16. A pharmaceutical composition comprising acompound of any one of claims 1-15 and a pharmaceutically acceptablecarrier.
 17. A method for treating, controlling or preventing obesity ina mammalian patient in need of such treatment which comprisesadministering to said patient a therapeutically effective amount of acompound of claim
 1. 18. A method for treating, controlling, orpreventing non-insulin dependent (Type 2) diabetes mellitus in amammalian patient in need of such treatment which comprisesadministering to said patient a therapeutically effective amount of acompound of claim
 1. 19. A method for treating, controlling orpreventing hyperglycemia in a mammalian patient in need of suchtreatment which comprises administering to said patient atherapeutically effective amount of a compound of claim
 1. 20. A methodfor treating, controlling or preventing lipid disorders, hyperlipidemia,or low HDL in a mammalian patient in need of such treatment whichcomprises administering to said patient a therapeutically effectiveamount of a compound of claim
 1. 21. A method for treating, controllingor preventing hypercholesterolemia in a mammalian patient in need ofsuch treatment which comprises administering to said patient atherapeutically effective amount of a compound of claim
 1. 22. A methodfor treating, controlling or preventing hypertriglyceridemia in amammalian patient in need of such treatment which comprisesadministering to said patient a therapeutically effective amount of acompound of claim
 1. 23. A method for treating, controlling orpreventing dyslipidemia and/or low HDL cholesterol in a mammalianpatient in need of such treatment which comprises administering to saidpatient a therapeutically effective amount of a compound of claim
 1. 24.A method for treating, controlling or preventing atherosclerosis in amammalian patient in need of such treatment which comprisesadministering to said patient a therapeutically effective amount of acompound of claim
 1. 25. A method of treating, controlling or preventingone or more diseases, disorders, or conditions selected from the groupconsisting of (1) obesity, (2) non-insulin dependent diabetes mellitus(NIDDM), (3) hyperglycemia, (4) low glucose tolerance, (5) insulinresistance, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia,(9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDLlevels, (12) high LDL levels, (13) atherosclerosis and its sequelae,(14) vascular restenosis, (15) irritable bowel syndrome, (16)inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, (17) other inflammatory conditions, (18) pancreatitis, (19)abdominal obesity, (20) neurodegenerative disease, (21) retinopathy,(22) neoplastic conditions, (23) adipose cell tumors, (24) adipose cellcarcinomas, such as liposarcoma, (25) prostate cancer and other cancers,including gastric, breast, bladder and colon cancers, (26) angiogenesis,(27) Alzheimer's disease, (28) psoriasis, (29) acne vulgaris, (30) otherskin diseases and dermatological conditions modulated by PPAR, (31) highblood pressure, (32) Syndrome X, (33) ovarian hyperandrogenism(polycystic ovarian syndrome), and other disorders where insulinresistance is a component, said method comprising the administration ofan effective amount of a compound of claim
 1. 26. A method of treating,controlling or preventing one or more diseases, disorders, or conditionsselected from the group consisting of (1) obesity, (2) non-insulindependent diabetes mellitus (NIDDM), (3) hyperglycemia, (4) low glucosetolerance, (5) insulin resistance, (6) lipid disorders, (7)dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10)hypercholesterolemia, (11) low HDL levels, (12) high LDL levels, (13)atherosclerosis and its sequelae, (14) vascular restenosis, (15)irritable bowel syndrome, (16) inflamatory bowel disease, includingCrohn's disease and ulcerative colitis, (17) other inflammatoryconditions, (18) pancreatitis, (19) abdominal obesity, (20)neurodegenerative disease, (21) retinopathy, (22) neoplastic conditions,(23) adipose cell tumors, (24) adipose cell carcinomas, such asliposarcoma, (25) prostate cancer and other cancers, including gastric,breast, bladder and colon cancers, (26) angiogenesis, (27) Alzheimer'sdisease, (28) psoriasis, (29) acne vulgaris, (30) other skin diseasesand dermatological conditions modulated by PPAR, (31) high bloodpressure, (32) Syndrome X, (33) ovarian hyperandrogenism (polycysticovarian syndrome), and other disorders where insulin resistance is acomponent, said method comprising the administration of an effectiveamount of a compound of claim 1, and an effective amount of one or moreother compounds selected from the group consisting of: (a) insulinsensitizers including (i) PPARγ agonists such as the glitazones (e.g.troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and thelike), and compounds disclosed in WO97/27857, 97/28115, 97/28137 and97/27847; (ii) biguanides such as metformin and phenformin; (iii)protein tyrosine phosphatase-1B (PTP-1B) inhibitors, and (iv) dipeptidylpeptidase IV (DP-IV) inhibitors; (b) insulin or insulin mimetics; (c)sulfonylureas such as tolbutamide and glipizide, or related materials;(d) α-glucosidase inhibitors (such as acarbose); (e) cholesterollowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin,itavastatin, ZD-4522 and other statins), (ii) sequestrants(cholestyramine, colestipol, and dialkylaminoalkyl derivatives of across-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a saltthereof, (iv) PPARα agonists such as fenofibric acid derivatives(gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dualagonists, such as KRP-297, (vi) inhibitors of cholesterol absorption,such as for example beta-sitosterol, (vii) acyl CoA:cholesterolacyltransferase inhibitors, such as for example avasimibe, and (viii)anti-oxidants, such as probucol; (f) PPARδ agonists such as thosedisclosed in WO97/28149; (g) antiobesity compounds such as fenfluramine,dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5inhibitors, and β₃ adrenergic receptor agonists; (h) an ileal bile acidtransporter inhibitor; and (i) agents intended for use in inflammatoryconditions such as aspirin, non-steroidal anti-inflammatory drugs,glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors.27. A method for the treatment, control, or prevention of one or moreconditions selected from inflammatory conditions, inflammatory boweldisease, Crohn's disease, and ulcerative colitis, which method comprisesadministering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of claim
 1. 28. A methodfor treating, preventing or controlling atherosclerosis in a mammalianpatient in need of such treatment comprising the administration to saidpatient of an effective amount of a compound of claim 1 and an effectiveamount of an HMG-CoA reductase inhibitor.
 29. A pharmaceuticalcomposition for the treatment, prevention or control of atherosclerosis,comprising: (1) a compound according to claim 1, (2) an HMG-CoAreductase inhibitor, and (3) a pharmaceutically acceptable carrier. 30.A pharmaceutical composition comprising (1) a compound according toclaim 1, (2) one or more compounds selected from the group consistingof: (a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like), and compounds disclosed in WO97/27857,97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin andphenformin; (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,and (iv) dipeptidyl peptidase IV (DP-IV) inhibitors; (b) insulin orinsulin mimetics; (c) sulfonylureas such as tolbutamide and glipizide,or related materials; (d) α-glucosidase inhibitors (such as acarbose);(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, itavastatin, ZD-4522 and other statins), (ii) sequestrants(cholestyramine, colestipol, and dialkylaminoalkyl derivatives of across-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a saltthereof, (iv) PPARα agonists such as fenofibric acid derivatives(gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dualagonists, such as KRP-297, (vi) inhibitors of cholesterol absorption,such as for example beta-sitosterol, (vii) acyl CoA:cholesterolacyltransferase inhibitors, such as for example avasimibe, and (viii)anti-oxidants, such as probucol; (f) PPARδ agonists such as thosedisclosed in WO97/28149; (g) antiobesity compounds such as fenfluramine,dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5inhibitors, and β₃ adrenergic receptor agonists; (h) an ileal bile acidtransporter inhibitor; and (i) agents intended for use in inflammatoryconditions such as aspirin, non-steroidal anti-inflammatory drugs,glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors;and (3) a pharmaceutically acceptable carrier.